Genetic linkages have been found to a number of neuropsychiatric disorders. In many cases, these discoveries will allow the development of presymptomatic diagnostic tests. Such testing will enable researchers to study the evolution of disease in those determined to be at high genetic risk. More importantly, presymptomatic detection of disease will guide treatment, early intervention, and prevention efforts. There has been great concern, however, about potential harmful effects of disclosing high genetic risk, especially for currently-incurable illnesses. A research program on testing for Huntington's disease (HD) using linked chromosome-4 markers was initiated in 1986. The purpose of this research has been to determine: 1) whether those with and without the linked DNA marker differ in their baseline neuropsychological and psychiatric characteristics, 2) the psychological and social consequences of presymptomatic diagnosis, 3) whether baseline characteristics can predict those consequences in individual cases, and 4) whether pre- testing education and counseling and post-test clinical follow-up can prevent or palliate morbid responses. To date, 74 healthy people at risk for HD have had informative tests, and another 42 who want genetic testing are in the protocol. In the proposed five-year continuation of this program, 90 new at-risk subjects will be entered into the testing protocol. All subjects will continue to be evaluated neurologically, psychiatrically, and neuropsychologically at regular intervals after disclosure of DNA test results. This application also contains two new initiatives. First, we will examine regional cerebral blood flow using the (15)O-labeled water PET technique in those subjects who test positive for the HD marker when they begin to display subtle changes in neurologic, affective, or cognitive status. This will enable us to determine which minor symptoms after testing herald disease onset, and will allow us to test hypotheses concerning the association of regional cerebral blood flow alterations with particular aspects of the clinical syndrome. The second new initiative consists of data analytic studies on the calculation of risk for HD based on linkage results. Using both real data from tested pedigrees and simulated data, the influence on estimation of risk of such factors as number of markers used, assumed allele frequencies, errors in ascribing paternity, and misdiagnosis of HD in relatives will be evaluated.